TWI328573B - Novel cyclohexyl sulphones - Google Patents

Description

1328573 A7 B7

The invention relates to a novel class of compounds, salts thereof, and pharmaceutical combinations therewith. In particular, the method of the present invention and its use for human therapeutic use relate to novel domains which can be adapted by r-secretase and are therefore useful for treating or preventing Alzheimer's disease. Alzheimer's disease (ad) is the most common state of dementia. Although 1% of people over the age of 65 are mainly suffering from senile diseases, AD fluid affects a large number of young patients with genetic factors. This is a neurodegenerative disorder characterized by a gradual loss of memory and cognitive ability, and a pathological feature of depositing extracellular plaques in the patient's skin and associated brain regions. These spots mainly include fibril agglutination of the cold-amyloid peptide (A /3). The secretory enzyme containing the putative 7 _ secretin enzyme in the processing of amyloid precursor protein (App) to form A cold has been well documented in the literature and is reviewed, for example, in WO 01/70677. The compounds in the literature that have inhibitory activity against γ-secretase (measured by cell-based assays) are reported to be relatively small. It is reviewed in WO 01/70677. Many related compounds are peptides or peptide derivatives. The present invention provides a new class of non-peptide compounds which can be used to treat or prevent Ad by a putative 7 • secretin enzyme regulating sputum processing thereby slowing sputum production. The present invention provides a compound of formula I:

Where: m is 0 or 1: 174 paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1328573 A7 B7 V. Invention description (2) Z stands for CN, 0R2a ' (:021123 or CON( R2a) 2 ;

Rlb represents hydrazine, C, .4 alkyl or OH: RU represents HSCm alkyl;

Ar1 represents a phenyl or pyridyl group, each of which may have a 〇_3 independently selected from the group consisting of a disk, CN, N02, CF3, OH, OCF3 'C, .4 alkoxy or C|.4 alkyl (see a substituent having a substituent selected from the group consisting of halogen, CN, N〇2, CF3, 〇11 and CU4 alkyl;

Ar2 represents a phenyl group which is substituted by a peptidin at the 2- and 5-positions; R2a represents an anthracene, a Cw alkyl group, a C3.6 cycloalkyl group, a C3_6 cycloalkyl C, a .6 alkyl group, a C2.6 alkenyl group, Any one optionally has a substituent selected from the group consisting of halogen, cn, N02, CF3, OR2b, C02R2b, N(R2b)2, CON(R2b)2, Ar and COAr: or R2a represents Ar; or two R2a and The bonded nitrogen atoms together form an N-heterocyclic group with 〇-4 independently selected from = 〇, = s, halogen, Cm alkyl, CN, N〇2, CF3, OH, Cm alkoxy, Cm Alkoxycarbonyl, C〇2H, amine, C,-4 alkylamino, bis(CN4 alkyl)amine, amine sulfhydryl, Ar and COAr substituents; R2b represents hydrazine, Cw alkyl , C3-6 cycloalkyl, C3.6 cycloalkyl Cw alkyl 'C2.6 alkenyl, any of which may optionally be selected from the group consisting of halogen 'CN, N02, CF3 ' OH, C, -4 alkoxy a substituent of Ci.4 alkoxycarbonyl, CO 2 H, an amine group, a Cu alkylamino group 'di(Cm alkyl)amino group, an amine fluorenyl group, Ar and COAr; or R 2b represents Ar; or two R2b, together with the nitrogen atom to which it is bonded, forms an N-heterocyclic group with 0-4 independently selected from = 〇, =S, halogen, Cu4 alkyl, CN, N 2. CF3, OH, CU4 alkoxy, Ci.4 alkoxycarbonyl, C〇2H, amine, C!-4 alkylamino, bis(Cm alkyl)amine, aminoguanidine-6 - 175 paper scales applicable to China National Standard (CNS) A4 specifications (210X297 public) · 1328573 A7 B7 V. Description of invention (3) Substituents for base, Ar and COAr;

Ar represents a stupid or heteroaryl group having 〇-3 selected from halogen, c14 alkyl, CN, N02, CF3, OH, C, .4 alkoxy, CN4 alkoxycarbonyl, amine, Ci. a substituent of a 4-alkylamino group, a di(C|_4 alkyl)amino group, an amine fluorenyl group, a c14 d-ylaminomethyl fluorenyl group, and a bis(Cm alkyl)aminocarbamyl group; or a pharmaceutical thereof Acceptable salt. When the variables in Formula I or the substituents thereof occur more than once, the individual occurrences of the variables are independent of each other unless otherwise stated. As used herein, the expression "Ch alkyl", wherein X is an integer greater than 1, represents a straight-chain and branched alkyl group in which the number of carbon atoms is in the range of 丨 to ^^. The particular alkyl group contains a methyl group, an ethyl group. , n-propyl, isopropyl and tert-butyl. Derivatives such as "C2·6 alkenyl", "hydroxy C, · 6 alkyl,", "heteroaryl c 〇 〇 2 · 6 alkyne The "" and "cw alkoxy" groups are structured in a similar manner. - "C: 3.6 cycloalkyl" as used herein refers to an early ring or fused bicyclic hydrocarbon ring system comprising from 3 to 6 ring atoms. Examples include cyclopropyl, decyl, cyclohexyl and cyclohexyl. Isobutyl, cycline, as used herein, "c3.6 ring-based C|-6-based, the formula includes a group, a cyclobutyl fluorenyl group, a cyclopentyl fluorenyl group, and a cyclohexylmethyl group. N-heterocyclic group, the meaning means a ring or polycyclic ring system of up to 1 ring atom selected from C, wherein not all of the constituent groups and at least one of the ring atoms is nitrogen and via the ring nitrogen bond ^ " Fang N-heterocyclic group is a 4.6-membered monocyclic system, such as 吖丁1. It is preferred to slightly bite the base, mercapto, thiophenanyl, benzyl, oxazolidine Base, base, oxazolidine scale applicable to China National G (CNS) A4 specifications (210X 2 丄 love 13285573 A7 B7 invention description used herein "heteroaryl, meaning that up to 1 选自 selected from C, N, a J singular or polycyclic ring system of a ring atom of 8 and at least one of which constitutes a ring is aromatic and at least one of the ring atoms is not carbon. Preferably, the heteroaryl group is a 5 or 6 membered monocyclic system such as pyridyl , hydrazine, pyrimidinyl, pyridyl, pyrrolyl, furyl, exemplyl, pyrazolyl oxazolyl, isoxazolyl, pyrazolyl, isoxazolyl, imidazolyl, oxadiazole base , triazolyl and oxadiazolyl. Further examples of heteroaromatics include tetrazole, 1,2,4-trin and 1,3,5-three wells. As used herein, "halogen," contains fluorine, gas, Bromine and iodine, among which fluorine and gas are preferred. For pharmaceutical use, the compound of formula I may advantageously be in a pharmaceutically acceptable salt state, but other salts may be used in the preparation of the compound or a pharmaceutically acceptable salt thereof. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts such as with salts =, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid a benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. a salt formed, and when the compound of the present invention has an acidic group, is a sodium, potassium, calcium or magnesium salt, and a salt formed with a suitable organic ligand such as a quaternary ammonium salt or a pyridinium salt. The compound of the present invention contains at least An asymmetric center, which can thus exist as an enantiomer. The compounds of the invention carry two or more asymmetry, which in turn can exist as diastereomers. a mixture of matter and any ratio thereof is included in the scope of the present invention No (IV) 存在 There is an asymmetric center, and some compounds of the present invention may exist as enantiomers due to the asymmetry of the whole molecule. It is understood that the enantiomers and mixtures thereof in any ratio in this example are included. Within the scope of the present invention, it is indicated that the structural formula of such a knife is required to represent the two possible enantiomeric 177 paper sizes. "Ti s Green Standard (CNS) - 1328573 A7 广_ B7 V. Invention Description ( 5~) " ------ ' Unless otherwise stated. In the compound of formula I, Ar1 represents a phenyl or pyridyl group optionally substituted, especially a phenyl or 3-pyridyl group optionally substituted. Preferably, it is selected from a stupid group substituted at the 4-position by a halogen, a fluorenyl group or a difluoromethyl group, and a stupid group substituted by a halogen at the 3_ and 4_ positions.

Ar2 is preferably a 2,5-difluorophenyl group. In a particularly preferred embodiment, Ar1 is 4-phenylphenyl or 4-trifluoromethylphenyl and Ar2 is 2,5-difluorophenyl. • Rule 11) typically represents hydrazine, methyl or OH, preferably η. The ruler typically represents hydrazine or methyl, preferably η. When m is 1, then 11|1> and 1^. Preferably, they do not simultaneously represent an alkyl group. Particularly good R2a comprises fluorene, phenyl, pyridyl, c:3·6 cycloalkyl (such as cyclopropyl, cyclobutyl and cyclopentyl), C3·6 cycloalkyl Cm alkyl (such as cyclopropyl a linear or branched Cl 6 alkyl group substituted with CF3, Ar, 〇R2b, N(R2b)2, C02R24C0N(R2b)2, optionally with a C2-6 alkenyl group (e.g., allyl). An example of the N-heterocyclic group represented by N(R2)2 includes a t-bottom-丨-based group (as the case may be OH, C02H, C02CU4 alkyl, Me or Ph), and a slightly cultivated _1_base (as appropriate) Or Ph substituted), "Lin-4-yl, sulfur?|> Lin-4-yl, l,l-dioxothiomorpholin-4-yl, 2-oxoimidazolidin-1-yl, 5,5-Dimethyl-2,2-dioxocarbazide-3-yl, 2,5-oxo-flavor <» siting 1-yl, 2-oxo<» Sitting bite _3 · base, 2 · oxygen generation? More than bite-1-yl and 2-oxo" than bite-l-yl. R2»> typically represents η or Cl4 alkyl. When Z stands for OR2a 'Min 23, it stands for Η, Ar (especially than bite base), hospital base (such as thiol, ethyl, propyl or butyl), or substituted alkyl (especially CH2Ar · 9 - i paper scale适财目g家料(CNS) Α4 Specifications (21GX 297 mm) ' 1328573 A7 B7

5. Description of the invention (6) If the base or p is more than the base. When Z represents C〇2R2a '1123, it suitably represents a hydrazine or an alkyl group (e.g., methyl, ethyl, propyl or butyl). When Ζ represents CO^J(R2a)2 ’ 1123 independently represents 院 or, as the case may be, a substituted, cyclized, lyophilic or dilute group, or together represents a heterocyclic group. Very suitably, one R2a represents hydrazine and the other represents hydrazine, alkyl (such as decyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, tert-butyl or 1-ethyl) Propyl), alkenyl (such as olefinic propylene), cycloalkyl (such as cyclopropyl, cyclobutyl or cyclopentyl), cycloalkylalkyl (such as cyclopropyl fluorenyl) or substituted alkyl (such as a substituted base of Ar, especially 2-pyridylethyl ' 3 (imidazolyl) propyl or 2- phenylethyl, or an alkane substituted with CF 3 , C 〇 2 R 2 b or c 〇 N (R 2b) 2 Base, especially 2,2,2-trifluoromethyl, methoxycarbonylindenyl or aminoindenyl). Alternatively, the two R 2a groups form an N-heterocyclic group, such as morpholine, thiomorpholine, thiomorpholine-1,1·dioxide, 4-methylpipelinium 4_phenylpiped, piperidine, 4-Hydroxypiperidine or piperidine substituted at the 3- or 4-position with an alkyl group, especially 3- or 4-carboxypiperidine, 3- or 4-carboxycarbonyl piperidine, 3-carboxy-methyl piperidine and 3 - Ethoxycarbonyl_3_mercaptopiperidine. Examples of individual compounds according to formula I are provided in the examples section described below. The compounds of formula I have activity as modulators of Αρρ processing by r-secretase. The invention also provides a pharmaceutical composition comprising one or more compounds of the formula or an acceptable salt thereof and a pharmaceutically acceptable carrier. Preferably, the compositions are in unit dosage form such as tablets, pills, capsules, powders, granules, sterilized parenteral solutions or suspensions, metered aerosols or liquid sprays, drops

%•10- 1328573 A7 ___B7 V. INSTRUCTIONS (7) Agents, ampoules, transdermal patches, autoinjector devices or suppositories: for oral, parenteral, nasal, sublingual or rectal administration, or for Insufflation or inhalation. For the preparation of a solid composition such as a syringe, the main active ingredient is mixed with a pharmaceutical carrier such as those known in the art, such as those described in WO 〇 1/70677 to form a unit dosage form. Typical unit dosage forms contain from 1 to mg, such as 1 '2, 5, 16, 25, 50 or 100 mg of active ingredient. The spirulines or pills of the novel compositions may be coated or mixed to provide a dosage form which provides the advantage of prolonged activity' as described in WO 01/70677. The novel compositions of the present invention may be incorporated into a liquid dosage form for oral or injectable administration comprising an aqueous solution of a suitably flavored syrup, an aqueous or oily suspension, and a bridged emulsion containing an edible oil, as described in WO 〇 1/70677. The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for use in a human therapeutic method. Preferably, the treatment is for a condition associated with a non-amyloid. Preferably, the condition is a neurological disease associated with a non-amyloid deposit such as Alzheimer's disease. The invention further provides a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture or prevention of Alzheimer's disease. The use of medicine for diseases. Also disclosed is a method of treating an individual afflicted with or susceptible to Alzheimer's disease' comprising administering to the individual an effective amount of a hydrazine compound or a pharmaceutically acceptable salt thereof. For the treatment or prevention of Alzheimer's disease, the appropriate dose is about 〇〇1 to 250 mg/kg per day, preferably about 5 to 1 mg/kg per day, especially about 0. 1 to 50 per day. Mg/kg body weight. The compound can be administered 1 to 4 times a day, but in some cases, doses other than this limit can be used.

-11 -

Ϊ 328573 A7 B7 V. INSTRUCTIONS (8) Compounds of formula I wherein m is deuterium and z is C02R2a or CON(R2a)2 may be coupled via carboxylic acid (1) (respectively) to R2aOH or HN(R2a)2:

Among them, Ar1, Ar2, Rlc and R2a have the same meanings as described above. Any standard coupling technique can be used' including the use of a coupling agent such as dimercaptoaminopyridine, hydroxy s-triazole, dicyclohexylcarbodiimide, carbonyldiimidazole, and the like. In a preferred method, the acid is converted to the corresponding helium (e.g., treated with turmeric in a DMF solution) and reacted directly with the desired nucleophilic group. In another preferred method, the acid is converted to an active ester derivative such as pentafluorophenol (e.g., in the presence of dicyclohexylcarbodiimide) and the intermediate is reacted with the desired nucleophilic group. The acid (1) is obtained by hydrolysis of the ester (2), generally under basic conditions, such as LiOH in an ethanol solution:

Wherein R2 represents an alkyl group such as a methyl group or an ethyl group, and Ar1, Ar2 and a ruthenium have the same meanings as defined above. The ester (2) can be obtained by reduction of the alkylene derivative (3), and then, when the ruler is not ruthenium, (C!·4 alkyl)-L (wherein L is a leaving group, especially bromine or Iodine) alkylation: This paper scale applies to the gg standard (CNS) Α 4 specification (21GX297 public) ' ------------ 1328573 A7 B7 V. Description of the invention

At Ai^SQ

CHCO, (3) wherein Arl, Ar2 and R2 have the same definitions as described above. The reduction can be carried out using sodium borohydride and nickel (II) vapor in ethanol, and the ester can be treated at low temperature in a non-protic solvent by a strong base such as sodium bis(trimethyldecyl) decylamine. 2, and if necessary, alkylate, then treated with (. 4 alkyl) and warmed to room temperature. If necessary, the unsaturated ester (3) can be hydrolyzed to the corresponding acid and 'borrowed with HN before olefin bond reduction ( The R2a) 2 reaction is converted to a guanamine. The unsaturated ester (3) is obtained by condensation of a ketone (4) with Ph3P=CHC02R2:

Wherein Ar1, Ar2 and R2 have the same definitions as defined above, and the ketone (4) is de-enketoped by the enol (5) to obtain 'the subsequent reaction (6) with at least two equivalents of the acyl acid (7) And formed:

Ar^CHjj-SO^Ar1 (6) ^^CC^R2 (7) wherein Ar1, Ar2 and R2 have the same definitions as described above. The decarboxylation reaction can be carried out by heating in DMSO at 150t in the presence of sodium carbonate and water, and the reaction of (6) and (7) can be carried out in an inert solvent such as thF at a peripheral temperature such as - 13- 1 This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1328573 A7 B7 V. Description of invention (1〇) ' -- Conducted in the presence of potassium tributoxide. Sulfone (6) is prepared by oxidation of thioether AP-CH^SA^S), which is followed by thiol Ar1 SH(9) and sulfhydryl derivative Ar2-CH2_L(10) (wherein L is the leaving gas or Bromine and Ar1 and Ar2 are formed as described in the above reaction. The reaction between (9) and (1) is carried out in an inert solvent such as di-methane in the presence of a base such as triethylamine, and (8) is emulsified to (6). It is also carried out in an inert solvent such as di-halogen methane. Compounds of formula I wherein m is 0 and Z is CN or OR2a can be obtained by reacting the acid g|(:ii) (individually) with cyanide or R2aOH:

Wherein L1 represents a sulfonate leaving group (e.g., methanesulfonate, tosylate or trifluorosulfonate) and Ar1 'Ar2, 111<: and R2a have the same definitions as defined above. The displacement reaction can be carried out in DMF at elevated temperature, e.g., about 80 ° C. When the nucleophilic group is R 2a OH, it is preferred to treat it with sodium hydride prior to the reaction with (11) to produce the corresponding anion. The sulfonate (11) is prepared by reacting an alcohol (12) with a suitable sulfonium gas (e.g., under anhydrous conditions in the presence of a tertiary amine).

(12) The alcohol (12) is derived from the hydride of the olefin U3): • 14- 1328573 A7 B7 V. Description of the invention (11)

Wherein Ar1, Ar2 and Rlc have the same definitions as described above. The method generally comprises reacting with borane in THF at room temperature, followed by treatment with an alkali hydrogen peroxide and separation of the desired cis isomer, terpene (13), from ketone (4) and Ph3P=CHRlc, (wherein Rlc has the same definition as defined above) is prepared by condensation. Another route in which the alcohol (12) of RU&H is obtained comprises the reduction of the ketone (4) (eg, using a shed hydride) to the corresponding secondary alcohol (丨4), The alcohol (14) is converted to the corresponding sulfonate (or equivalent leaving group), and the nucleophilic group is replaced with a cyanide ion to hydrolyze the resulting nitrile to the corresponding carboxylic acid, followed by reduction to the primary alcohol. The hydrolysis is generally carried out under acidic conditions (e.g., in a mixture of acetic acid and concentrated HCl at 11 Torr. (:) and the reduction is preferably carried out by sequential treatment with isobutyl methacrylate and borohydride in Thf. The compound of the formula I which is 1 and the ft. to ^^ or 44 can be obtained by oxidation of the alcohol (12) to the corresponding aldehyde or ketone, and the completion of the carbonyl group is as described above with the ketone (4) wherein m is The compound of the formula I is reacted in a manner related to, for example, an oxidation reaction of an alcohol (12) of RlcSH to obtain a corresponding cyclohexanecarboxaldehyde which is condensed with PhaP-CC^Et to obtain ethyl 2-cyclohexyl acrylate. Ethylene can then be hydrogenated to the corresponding ethyl 2-cyclohexylpropionate, which may optionally be alkylated and/or hydrolyzed to the corresponding acid, and/or converted to various guanamines or other ester derivatives, beta, which are not commercially available. In the above synthetic reaction scheme, the starting materials and reagents can be obtained by using the standard techniques of organic synthesis to obtain commercially available materials. It is necessary to know that many of the above synthetic reaction diagrams will produce a mixture of enantiomeric structures _ -15- 184 sheets of paper. The scale applies to the gg home material (CNS) Α 4 specifications (plus X297 public love) ------

Things. In particular, certain product practicables, the specific 5I butyl hydrazine in 1 is a mixture of cis and trans isomers, and the opposite side of the T substituent ring substituent. This mixture is available! Ipsilateral or chromatographic, a-mode cleavage such as segmental crystallization and preparation of certain compounds of the invention due to the presence of the right molecule. One or more pairs of palmar centers or by preparation can exist optical isomers. Compounds can be prepared by chiral or enantiospecific synthesis or by resolution to prepare individual enantiomers: such novel compounds, such as preparative standard techniques such as preparative HpLc, are resolved into (tetra) or by optical activity such as (. ············································································ Crystallization and free regeneration. The new lysate can also be resolved by the formation of diastereomeric or enamined amines, followed by chromatographic separation and removal of the palmitic auxiliary. During any of the above synthetic sequences, it may be necessary and / Or better protect any sensitive or reactive group on the molecule. This can be achieved by means of a customary protecting group, as described in Organic Chemical Protection, edited by jFw Mc〇mie, 卩丨(3)(10), 1973; and TW Greene & PGM Wuts, Organic Synthesis Protection Group, John Wiley & Sons, 1991. The protecting group can be removed at a convenient, convenient stage using methods known in the art. Suitable methods for analyzing the extent of activity of the compounds of the invention for 7 • secretin are disclosed in WO 01/70677 and Biochemistry, 2000, 39(30), 8698-8704. Examples of the invention each have an ED of less than 10 μΜ, preferably less than 1 μΜ and preferably less than 1 〇〇ηΜ in at least one of the above analyses. The following examples illustrate the invention. 1328573 A7 ______B7 V. Description of invention (13)

Dehydrated (MgS〇4) and dried to dryness. The product was purified by hexane-ethyl acetate mixture down through a silica gel plug. 5.12 grams.丨1^1^1411€0(:137.;23(411,3), 6.69-6.86 (3Η,m) and 4.04 (2Η, s). Sulfide (5.12 g, 0.018 mol) is soluble in two gases曱 ( (1 〇〇 ml) and treated with m-benzoic acid (14.3 g, 〇.〇42 mol (50% rated)) and stirred for 2 hours. The reaction was followed by Na2S2〇$(5 % solution, 1 () 0 ml), saline (5 〇 ml), sulphate dehydrated (MgS 〇 4) and evaporated to dry β | wind products were purified by dissolving in a mixture of hexa-acetic acid in acetonitrile. 3.6 g. 丨η NMR CDC13 7.61 (2H, d, J=8.6Hz), 7.45 (2H, d, J=8.6Hz), 7.13-7.08 (1H, m), 7.05-7.01 (1H, m), 7.05 -7.00 (1H,m), 6.99-6.87 (1H, m) and 4.36 (2H,s) » Intermediate 2

F3 -17- 1328573 A7 B7 V. INSTRUCTIONS (14) As an intermediate 1, 4-trifluoromethylthiophenol was used and a solid was obtained. Η NMR (360MHz, CDC13) δ 7.85-7.83 (2Η, m), 7.76-7.74 (2Η, m), 7.15-7.10 (1Η, m), 7.06-7.0 (1Η, m), 6.92-6.86 (1Η, m) and 4.46 (2H, s). Preparation example 1

Intermediate 1 (1 g ' 3.31 mmol) and decyl acrylate (〇 84 mL, 9.27 mmol) in tetrahydrofuran (3 mL) with potassium butoxide (364 mL, 1M in tetrahydrofuran) , 3.64 millimoles) is processed by drop. The reaction was stirred for 2 hours, diluted with ethyl acetate (1 mL) and washed with water (5 mL) and brine (50 mL). The organic phase was separated, dried (MgSO.sub.4) and evaporated to dryness. The product was purified on a silica gel eluted with hexane-ethyl acetate mixture (yield) π ι NMR CDC13 12.0 (1H, s), 7.41 (4H, s ), 7.06-7.0 (2H, m), 6.87-6.81 (1H, s), 3.81 (3H, s), 3.38 (1H, dd, J=3.2, 15.8Hz), 3.02-2.92 (2H, m), 2.52 (1H, dd, J=5.7, 18.5 Hz), 2.3-2.2 (1H, m)A 2.2-2.1 (1H, m). Preparation Example 2

Ester from Preparation Example 1 (1.0 g, 2.25 mmol) in dimethyl hydrazine (1 〇〇 | § 7 This paper scale applies to Chinese National Standard (CMS) A4 size (210X297 mm) 1328573 A7 B7 5. Description of the invention (15) ML) was treated with NaCl (0.3 g ' 4.96 mmol) and water (0.9 mL, 4.96 mmol) and heated at 150 ° C for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (100 mL). EtOAc EtOAc (EtOAc) The product was dissolved on a silica gel in a mixture of hexane-ethyl acetate. 0.5 grams. 1H NMR CDC13 7.43-7.37 (4H, m), 7.22-7.1 (2H, m), 6.97-6.9 (1H, m), 3.05-2.98 j; 2H, m), and, 2.61-2.53 (2H, m) . Preparation Example 3

Preparation of Intermediate 2 using the procedures of Preparations 1 and 2 gave a solid product (0.3 g). Towel NMR (360MHz, CDC13) δ 7.71-7.69 (2H, d, J=7.5Hz), 6.62-6.60 (2H, d, J=7.4Hz), 7.22-7.11 (2H, m), 6.95-6.88 (1H , m), 3.02-2.99 (2H, m), 2.63-2.54 (4H, m) and 2.25-2.16 (2H, m). Preparation Example 4 1U This paper method scale applies to China National Standard (CNS) A4 specification (210X297 mm)

Ethyl (diethoxyphosphonium sulfoxide) ethyl acetate (5.16 ml, 26 mmol) was added dropwise to sodium hydride (60% dispersion in mineral oil, 988 mg, 24.7 mmol) of 13285573 A7 B7 , invention instructions (16 tetrahydrofuran (60 ml) in a liquid and the mixture was stirred at room temperature for 1 hour. Within 20 minutes: add the ketone of Preparation 2 (5 grams, 13 millimoles) to four... (50 ml) of the solution, and the mixture was searched at room temperature for (four) hours. Add water and acetic acid B S | extraction. The combined organic portions were washed with water, dehydrated (MgS04) and evaporated under reduced pressure. Purification by chromatography <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> NMR (400 MHz, CDC13) δ 7.41-7.36 (4 Η, m), 7.18-7.13 (1Η, m), 7.11-7.05 (1H, m), 6.93-6.86 (1H, m), 5.64 (1H, s), 4.14-4.10 (2H, m), 3.99-3.96 (1H, m), 2.91 -2.80 (2H, m), 2.42-2.38 (1H, m), 2.31-2.04 (3H, m), 1.89-1.7 8 .(1H, m), 1.28-1.24 (3H, m) Preparation Example 5

(a)

(b) The ketone from Preparation 2 (O.1 g, 〇 26 mmol) was taken from EtOAc (2 mL). The reaction was quenched with EtOAc (1 mL, EtOAc) (EtOAc)EtOAc. The cis and trans products were purified by dissolving the hexane-ethyl acetate mixture on a silica gel. (a) (trans)0.052 *lHNMRCDCl3 7.39-7.33 (4H,m),7.11-7.02 (2H, m), 6.88-6.82 (1HS m), 3.80-3.73 (1H, m), 2.80-2.60 -20 The paper size is based on the Chinese National Standard (CNS) A4 specification (210x 297 mm) 1328573 A7 B7 V. Description of invention (17) (2H, m), 2.22-2.16 (2H, m), 2.08-2.04 (2H, m), 1 53 (1H br) and 1.27-1.13 (2H, m). (b) (cis) NMR (CDC13) 7.40 (4H, s), 7.16_7 〇3 (2H, m), 6.90-6.83 (1H, m), 3.97-3.95 (1H, m), 3.77-3.68 ( 1H, m), 3.51-3.49 (1H, m), 2.61-2.53 (2H, m), 1.914.83 (2H, m) and 1.50-1.42 (2H, m). *Preparation Example 6

Trans-cyclohexanol (2.7 g, 6.9 mmol) from Trial Preparation 5 and triethylamine (1.45 mL, 10.3 mmol) in dioxane (50 mL) with decanesulfonium (0.645) ML, 8.9 millimoles) is processed at -30 °C. After 30 minutes, the mixture was washed with EtOAc EtOAc m. The solid was dispersed in diethyl ether to give the methanesulfonate (2.6 g). 1H NMR (CDC13) 7.40-7.37 (4H, m), 7.12-7.07 (2H, m), 6.92-6.83 (1H, m), 4.78-4.65 (1H, m), 2.96 (3H, s), 2.88-2.52 (2H, m), 2.29-2.21 (4H, m) and 1.59-1.47 (2H, m) » Preparation Example 7

Trans methanesulfonate (103 mg, 0.22 mmol) dissolved in Preparation Example 6 This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1328573 A7 _____B7 V. Description of invention ( 18) Toluene (20 ml) and a pre-azeotropic sample added to tetrabutylammonium cyanide (354 mg, 132 mmol), and the mixture was warmed to 7 〇 for 18 hours and then cooled to room temperature. The solution was diluted with water (10 mL) and washed with EtOAc EtOAc. The organic phase was washed with brine (1 ml), dehydrated (MgS 4) and evaporated. The obtained transparent oil was purified by enthalpy gel column chromatography eluting with 1 〇 2 〇% ethyl acetate in hexane to obtain cyanide 4 NMR (CDC13) 7.42-7.30 (4H, S), 7.10-7.05 (2H, m), 6.89-6.84 (1H, m), 2.88-2.86 (1H, m), 2.76-2.72 (2H, m), 2.52-2.45 (1H, m), 2.12-2.07 (1H, m) and 1.56- 1.49 (1H,m) » Preparation Example 8

The fluoride of Preparation Example 7 (143 mg &apos; 0.36 mmol) was dissolved/suspended in a mixture of glacial acetic acid (10 mL) and concentrated HCl (6 mL) and was warmed for 15 min. The mixture was cooled, diluted with ethyl acetate and washed with water &lt;RTI ID=0.0&gt;&gt; The residue (丨53 mg) was purified by preparative tic (5% sterol dioxane / 1 〇 / EtOAc). iH NMR (CDCl3) 7.38-7.35 (4H, s), 7.08-7.06 (2H, m), 6.90-6.84 (1H, m), 2.65- 2.58 (2H, m), 2.38-2.33 (3H, m) and 1.75-1.49 (4H, m). Preparation Example 9

-22- igt This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328573 A7 ____ B7 V. Description of invention (19) Cyanide from Preparation Example 8 (50 mg, 0.12 mmol) ) Dissolved in a mixture of tetrahydrofuran (4.5 ml) and water (0.5 ml) at 2 〇β (: searched off. Mixed people treated with hydrogen peroxide (20 ml, 0.6 mmol) followed by hydrogen Oxidation in milligrams, 0.25 millimoles) for 2 hours. Perylene peroxide (2 mL, 〇 6 mmol) was added followed by lithium hydroxide (6 mg, 0.25 mmol) and the mixture was stirred at room temperature for 72 hours. The mixture was cooled, diluted with ethyl acetate and washed with EtOAc EtOAc EtOAc. This crude residue (51 mg) was purified by preparative tic (20% ethyl acetate). NMR (CDC13) 7.37 (4H, s), 7.10-7.02 (2H, m), -6.90-6.84 (1H, m), 5.57 (2H, brs), 2.54-2.48 (3H, m), 2.43-2.39 (1H, m), 2.19-2.15 (2H, m) and 1.62-1.50 (3H, m). Example 1

Sodium hydride (313 mg, 8.23 mmol) was added to prepare the saturated ester of Preparation 4 (3.74 g, 8.23 mmol) and vaporized nickel (11) (2.67 g, 20.6 mmol) of ethanol ( 1 〇〇 ml) mixture was stirred at room temperature for 20 minutes, then water (100 mL) was added. The mixture was filtered through HyfioTM and washed with ethyl acetate and ethyl acetate. The solvent and residue were evaporated under reduced pressure and partitioned between ethyl acetate and water. The organic layer was collected, dehydrated (MgS04) and evaporated to remove solvent. The residue was purified by flash chromatography on silica gel eluting with hexane: EtO Ac (85: 15) to obtain the oily cis isomer (1.36 g, 36%), -23-192 paper The scale applies to the Chinese National Standard (CNS) A4 specification (210X297 public love) 1328573 A7 ______B7 _ _____ V. Description of invention (20) 'H NMR (400MHz, CDC13) δ 7.37-7.30 (4Η, m), 7.09-7.00 ( (2H, m) (1H, m), 1.76-1.71 (2H, m), 1.57-1.48 (4H, m), 1.27 (3H, t, J = 7.1 Hz); and a slower flowing oily trans isomer (200 Mg, 5.3%). Example 2

F

Lithium hydroxide (350 mg, 14.57 mmol) was added to a solution of the cis ester of Example 1 (1.33 g &apos; 2.91 mmol) in ethanol (4 mL). The mixture was degassed and stirred at room temperature under nitrogen for 5 hours. The mixture was poured into aqueous HCl (1M) andEtOAc. The organic extract was dried (M.sub.4). 1H NMR (400MHz, CD3OD) δ 7.5, 7.49 (2H, m), 7.40-7.37 (2H, m), 7.19-7.10 (2H, m), 7.00-6.94 (1H, m), 2.51-2.35 (6H, m), 2.13-2.10 (1H, m), 1.78-1.74 (2H, m), 1.57-1.50 (2H, m). Example 3

-24- ! 93 paper size applicable to China National Standard (CNS) A4 specification (210X297 public) 1328573 A7 B7 V. Description of invention (21) Example 2 acid (50 mg, 0. U7 mmol), morpholine (30 μl, 0.351 mmol), 1-hydroxybenzotriazole (24 mg, 0.176 mmol) and triethylamine (65 μL, 0.468 mmol) in tetrahydrofuran at room temperature under nitrogen Stir for 10 minutes. To the mixture was added 1 · (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45 mg, 0.234 mmol) and stirred for 24 hours. The mixture was poured into aqueous sodium hydroxide (1M) and ethyl acetate. Organic extraction, liquid extraction and dehydration (MgS04) and evaporation of solvent under reduced pressure. The residue was purified by flash column chromatography eluting with EtOAc EtOAc 4 NMR (400MHz, CD3OD) δ 7.50 (2Η, d, J 8.6Hz), 7.37 (2H, d, J 8.6Hz), 7.19-7.09 (2H, m), 7.00-6.93 (1H, m), 3.69- 3.63 (4H, m), 3.59-3.56 (4H, m), 2.55 (2H, d, J 7.4Hz), 2.47-2.39 (4H, m), 2.16-2.07 (1H, m), 1.78-1.74 (2H , m), 1.58-1·51 (2H, m) » m/z (ES+) (M+l) 498+500. Examples 4-15 Following the procedure of Example 3, the following compounds were replaced with the appropriate amine in place of morpholine.

-25- 194 Paper Size General Chinese National Standard (CNS) Α4 Specification (210X297 mm) 1328573 A7 B7 V. Description of Invention (22) Example • nr2 Structure MW m/z (ES+) (M+l) 4 -iTV 510 511 C25H29C1F2N203S 512 513 5 -Ό-Ο 572 573 C30H3IC1F2N2O3S 574 575 6 —f/ y~OH 511 512 C25H28ClF2N〇4S 513 514 7 „fj 532 533 〇C27H27C1F2N203S 534 535 8 —[Jh~^~ 535 536 C26H28C1F2N303S 537 538 9 567 568 —N )~C02Et C28H32C1F2N05S 569 570 10 567 568 V-\ 〇28出2(^21^053 569 570 C02Et 11 -T\ 567 568 C28H32C1F2N05S 569 570 C02Et 12 -T\ 567 568 w it〇 2Et C28H32C1F2N05S 569 570 13 o 495 496 C25H28CIF2N03S 497 498 14 _/Λ 581 582 C29H34C1F2N05S 583 584 * C02Et 15 _/Λ 581 582 W / t〇2Et C29H34CIF2N〇5S 583 584 -26- This paper scale applies to Chinese national standards ( CNS) A4 size (210X297 mm) 1328573 A7 B7

Example 16·33 by the following method, -etc.

Prepare the method by using the appropriate amine free base or amine salt before neutralization.

Dihydrophenyl)cyclohexaneacetic acid (0.35 mmol) of di-methane (5 ml) was stirred in a suspension, and added with hydrazine gas (0.05 ml, 〇57 mmol) and dimercaptocaramine (1 drop). After 30 minutes, the solution was evaporated to a small volume and added to a solution of the residue in dioxane (5 ml), and the desired amine (丨 75 mmol) solution was stirred for 2 min. The residue was purified by silica gel chromatography with increasing concentration of ethyl acetate-containing hexane (25%, 50%). The content of the product contained in the product was evaporated to obtain the product, and the amine was produced. Purification by chromatography on silica gel using an appropriate concentration of 'prepared' ethyl acetate, ethyl acetate or ethyl acetate containing decyl alcohol. 19$ This paper scale applies to China National Standard (CNS) Α4 specification (210X297 public) 1328573 A7 B7 V. Invention description (24)

Example No. R MS xn/z (M+H) mp· 16 NH-cyclobutyl. 482,484 192-193〇C 17 nh2 428,430 187-189 °C 18 NHMe 442,444 200-201 °C 19 NHEt 456,458 146-147〇 C 20 NH&quot;Pr 470,472 150-151 °C 21 NHiPr 470,472 124-125 °C 22 ΝΜθ2 456,458 23 NHCH2CH2Ph 532,534 24 NHCH2CF3 510,512 25 /~\/PNS( u,, o 546,548 26 NHCH2-cyclodecyl 482,484 187-188 °C 27 NH-cyclopentyl 496,498 182-183 〇C 28 NH-cyclopropyl 468,470 145-147 〇C 29 'NHnBu 484,486 oil 30 NHlBu 484,486 102-110 〇C 31 NHCH(Et)2 498,500 89-92 ° C 32 NH-allyl 468, 470 132-134 °C Example 33

-28- •IQ7 This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1328573 A7 B7 Description

Trifluoroacetic anhydride (0.056 ml) was added to a solution of EtOAc (EtOAc m. When 0.5 M-HC1 (aqueous solution) and ethyl acetate were added, the solution was searched for 2 hours at room temperature. The organic phase is dehydrated (MgS 〇 4) to evaporate to a small volume and purified by eluting with hexanes: ethyl acetate (5:1) to afford the desired product as a colorless solid. NMR NMR (360MHz, CDC13) δ 1.61-1,70 (2Η, m), 1.86-1.94 (2Η, m), 2.03-2.10 (1H, m), 2.42-2.45 (4H, m), 2.51 (2h d J 8.0 Hz), 6.8 (1H, m), 7.02-7.09 (2H, m), 7.30 (2H, d J 8.6 Hz), 7.36 (2H, d J 8.7 Hz).例 34

6jl (153 mg) of Preparation 8 was dissolved in anhydrous THF (1 mL) and cooled to 0. Triethylamine (61 microliters, 0.43 millimoles) and methotonic acid isobutyl vinegar (57 microliters '0.43 millimoles) were added and the mixture was stirred at 〇«c for 1 hour. The precipitate formed was removed by filtration and washed with 5 mL of anhydrous THF. The combined THF layer was cooled to oec and added with sodium borohydride (70 mg, 丨84 mmol) in water (2 mL) / sap liquid. After mixing for 30 minutes in 〇C, the reaction was acetonitrile. Dilute, wash with ammonium sulfate solution, sodium bicarbonate solution and brine, then dehydrate (MgS〇4) and evaporate to dryness. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)咕NMR (CDCh) 7 39_ 7.31 (4H, m), 7.10-7.01 (2H, m), 6.88-6.81 (1H, m), 3.71 (2H, •29- 1 % This paper scale applies to Chinese national standards ( CNS) A4 specification (210X297 public) 1328573 A7 B7_ V. Invention description (26) d, J=7.5Hz), 2.46-2.32 (4H, m), 1.90-1.85 (2H, m), 1.78-1.74 (1H , m) and 1.54-1.44. (2H, m). m/z = 423 [MNa]+. Example 3 5

Step (1): Add pentafluorophenol (1.5 equivalents) and DCC (1.5 equivalents) to the solution containing the acid of Example 2 (1 g) DCM (50 ml) and ethyl acetate:* (30 ml) Stir for 1 hour. The reaction mixture was evaporated in vacuo, taken in ethyl EtOAc and filtered. The filtrate was evaporated in vacuo to give a pentafluorophenol ester of sufficient purity for the next reaction. Step (2) A solution of pentafluorophenolate (155 mg, 0.25 mmol) prepared in the step (1) in DMF (3 ml) was added with glyceryl glycinate (125 mg, under nitrogen). 1.0 mmol, and triethylamine (0.15 ml). After 2 hours, the reaction was diluted with water and extracted with ethyl acetate (x3), washed with water, brine, dried (MgSO.sub.4), filtered and evaporated. Purification by column chromatography (1:1 EtOAc/EtOAcEtOAcEtOAcEtOAcEtOAcHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (1H, m), 1.67-1.71 (1H, m), 1.75-1.79 (2H, m), 1.91-1.95 (1H, m), 2.20-2.26 (1H, m), 2.41 (4H, d, J= 7.8 Hz), 3.77 (3H, s), 4.05 (2H, d, J=5.1Hz), 6.19 (1H, br), 6.79-6.85 (1H, m), 7.00-7.07 (2H, m), 7.30- 7.37 -30- tgq This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1328573 A7 B7 V. Description of invention (27) (4H, m). Example 36

The glycinate (50 mg, 01 mmol) prepared in Example 35 was dissolved in a 2M aqueous ammonia solution (3 mL) and heated to 50 ° C for 3 hours. After cooling to room temperature, the reaction mixture was evaporated mjjjjjjjj MS (EI+): 485 (MH+). Example 37

The alcohol of Example 34 (4 g, 10 mmol) was dissolved in dioxane (28 mL) and treated with Dess Martin Periodinane (4 g 66 g, 11 mmol) and the mixture was stirred for 45 min. The mixture was added with a saturated aqueous solution of sodium hydrogen sulphate ( </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The crude residue (4 g) was dissolved in anhydrous gas (100 ml) and treated with trisyl acetate (47 » _ · · g, 14 mmol) and stirred at room temperature for 16 hours. The evaporating agent and the residue were purified by elution with 10-20% ethyl acetate in hexane to obtain -31 - the paper size is applicable to Chinese national standard (CMS) Α4 specification (210X297 public) 1328573 A7 B7 V. Description of invention (28) Product. 1H NMR (CDC13) 7.37-7.36 (4H, m), 7.10-7.02 (3H, m), 6.87-6.83 (1H, m), 5.91 (1H, d, J=16Hz), 3.77 (3H, s), 2.55-2.45 (3H, m), 2.40-2.38 (2H, m), ΐ·95·ι·9〇(2H, m) and 1.65-1.52 (2H, m). Example 38

The alkene of Example 37 (3.6 g &apos; 9 mmol) was dissolved in ethyl acetate (35 mL). The bottle was degassed and then 10% palladium on carbon (400 mg) was added and the mixture was stirred in hydrogen for 45 minutes. The solution was filtered and evaporated over Celite. The obtained transparent oil was purified by preparative tic in 5% acetic acid ethyl acetate. The obtained oil was then purified by pyrolysis with 5-10% ethyl acetate to obtain the product β 1 η NMR. (CDCl3) 7.37-7.34 (4H, m), 7.08-7.00 (2H, m), 6.85-6.81 (1H, m), 3.67 (3H, s), 2.45-2.39 (4H, m), 2.33 (2H, t, J - 8.4 H z), 1 · 8 1 (2 H, q, J - 8.4 H z), 1 · 7 2 · 1.6 8 (2 H, m) and 1.60- 1·43 (3H, m) . Example 39

The ester of Example 38 (104 mg, 0. 23 mmol) was dissolved in a mixture of ethanol (10 mL) and water (3 mL) and stirred at 20 °C. The bottle was degassed and then the hydrogen oxidized chain (27 mg, 1.15 mmol) was added. The mixture was mixed for 3 hours at room temperature. Μ $ The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328573 A7 _ B7 V. Description of the invention (29) Next, add 1N hydrochloric acid and the mixture to ethyl acetate (2 X 50 ml) washing. The organic phase was washed with brine (50 ml), dehydrated (MgS04) and evaporated. The resulting oil was then purified by preparative tic in ethyl acetate to afford acid. NMR (CDC13) 7.37-7.30 (4H, m), 7.09-6.99 (2H, m), 6.85-6.79 (1H, m), 2.42-2.36 (6H, m), 1.85-1.79 (2H, m), 1.73 -1.69 (2H, m), 1.63-1.58 (1H, m) and 1.53-1.45 (2H, m). 'Example 40 . 2Θ2

The acid (52 mg, 0.118 mmol) of methane (2 mL) from Example 39 was treated with EtOAc (EtOAc (EtOAc) A drop of N,N-dimethylformamide was added and the solution was stirred for 2 hours. Subsequently, the solvent was removed in vacuo and the residue was dissolved in dichloromethane (1 mL). The solution was added dropwise to hydrazine ammonia (2 Torr, 2 mL). The reaction was evaporated in vacuo and the residue was purified eluting eluting eluting eluting The material was purified by preparative tic eluting with 100% ethyl acetate then recrystallised from hot hexane to afford product (7.4 mg, 14%). lH NMR (360MHz, CDC13) 1.45-1.53 (2H, m), 1.57-1.65 (1H, br), 1.70-1.75 (2H, m), 1.78-1.84 (2H, m), 2.32 (2H, t, J = 15.3 Hz), 2.38-2.44 (4H, br), · -2: 95 (3H, s), 3.02 (3H, s), 6.79-6.86 (1H, m), 7.00-7.09 (2H, m), 7.31-7.37 (4H,m) ; ms. (ES+), 470 (M+l), 294 (M+175). -33- This paper size applies to Chinese National Standard (CNS) A4 specification (210x 297 mm)

Binding '% 1328573 A7 B7 V. Invention Description (3〇) Example 41

The cis-ester of Example 1 (669 mg, 1.467 mmol) in tetrahydrofuran (14 mL) was cooled to -78 ° C to bis(trimethyldecyl) decylamine (22 mL, Μ 四 THF The solution was treated with 2.20 millimoles and the mixture was warmed to room temperature for 2 hours. Then at -20. Add f-based iodine (457 μl ' 7.36 mmol) to the mixture and continue to search for 'further to room temperature for 2 hours, when the β reaction is quenched with glacial acetic acid (132 μl, 2.20 mmol) Diluted with ammonium sulfate (50% in water, 80 mL) and extracted with ethyl acetate (3×1 mL). The combined organics were washed with EtOAc (EtOAc m. The material was chromatographed on silica gel eluting with EtOAc EtOAc (EtOAc) *H NMR (400 MHz, CDC13) 1.16 (3H, d, 3=6.9 Hz), 1.28 (3H, t, J=7.1 Hz), 1.45-1.51 (2H, m), 1.71-1.77 (2H, m) , 1.89-1.94 (1H, m), 2.28-2.48 (3H, br), 2.54-2.60 (1H, br), 2.70-2.74 (1H, m), 4.09-4.18 (2H, m), 6.77-6.84 ( 1H, m), 6.99-7.08 (2H, m), 7.26-7.36 (4H, m). Example 42

-34- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1328573 A7 B7_ _ V. Inventive Note (31) The ketone of Preparation Example 3, according to Preparation Example 4 and Examples 1 and 2 Program preparation. 'H NMR (360MHz, CDC13) 1.52-1.61 (2H, m), 1.76-1.81 (2H, m), 2.20-2.26 (1H, m), 2.39 (2H, d, J=7.6Hz), 2.40-2.50 (4H, m), 5.37 (1H, br), 5.51 (1H, br), 6.75-6.83 (1H, m), 7.01-7.08 (2H, m), 7.51 (2H, d, J=8.3Hz) and 7.64 (2H, d, J = 8.3 Hz). Example 43

Ammonia was used in the second step by the procedure of Example 35, and was prepared from the acid of Example 42. MS MH+ 462 (463). Example 44

Prepared from the ketone of Preparation Example 3 following the procedures of Preparations 5-8 and Examples 34, 37, 38 and 39. 'H NMR (360MHz, CDC13) δ 10.1 (1Η, m), 7.64 (2H, d, J=8.3Hz), 7.53 (2H, d, J=8.3Hz), 7.09-7.00 (2H, m), 6.83 -6.76 (1H, m), 2.50-2.37 (6H, m), 1.85-1.81 (2H, q, J=7.4Hz), 1.75-1.70 (2H,m), 1.63-1.59,(1H,m), 1.55-1.45 (2H, m). MS(EI+) 477 (MH+) » ‘,i .-· ·· · -35- __ lfi4 This paper size applies to China National Standard (CNS) A4 specification (210X297 public)

Claims (1)

Patent Application No. 132857S〇9iii8〇97 A8 Announcement Replacement of Chinese Patent Application (April 99) 3 ’ 08 __ ___D8 VI. Scope of Application 1. A compound of formula I, Wherein: m is 0 or 1; Z represents CN, OR2a, C02R2a4CON(R2a)2; Rlb represents Η; Ru represents HSCm alkyl; Ar1 represents 4-carbon phenyl or 4-trifluoromethyl phenyl; Ar2 represents 2 , 5-difluorophenyl; R2a represents hydrazine, Cu alkyl, c3.6 cycloalkyl, C3-6 cycloalkyl C! or C2·6 alkenyl', any of which may optionally be selected from c〇: a substituent of CON(R2b)2; R2b represents a hydrazine or a CN6 alkyl group or a pharmaceutically acceptable salt thereof. 2. A compound of the formula of claim 1, wherein z represents C0 R2a represents a hydrazine or a Cu alkyl group. 3) A compound of the formula of claim 1, wherein m is 1, wherein 4-chlorophenyl, r1c represents η, and z represents CO2H, or an I acceptable salt thereof. 4_ For example, the formula 第 compound of the first paragraph of the patent range, where ^ is 1, 79526-990408.DOC This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 6 Burning base R2b and 2R2aA ΑιΆ I medicine can be Ar% 1328573 A8 B8 C8 I------------ D8 VI. Application for patent garden table 4-difluorodecyl stupid base, Rlc stands for η, and ζ stands for c〇 2h, or a pharmaceutically acceptable salt thereof. The compound of the formula I of the first aspect of the patent, wherein m is 0, Ar 丨 represents 4 气 基 ’ ' R lc represents R Η, and Z represents CONH 2 , or a pharmaceutically acceptable salt thereof. 6. A compound of formula I according to claim 1 wherein m is 0, Ar1 represents 4-difluoroindolyl, Rlc represents hydrazine, and Z represents CONH2, or a pharmaceutically acceptable salt thereof. The compound of formula I of the scope of the patent application is wherein the m is O'Ar1 represents a gas group, Rlc represents hydrazine, and Z represents CQNHCH2CH3, or a pharmaceutically acceptable salt thereof. 8. A compound of formula I as claimed in claim 1 wherein m is 0, Ark epichlorophenyl phenyl 'RU stands for hydrazine, and Z represents CN, or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition for treating an individual suffering from or susceptible to Alzheimer's disease, comprising an effective amount of a formula of claim 1 or a pharmaceutically acceptable salt thereof. 10. A compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, for use in the treatment or prevention of Alzheimer's disease. 11. Use of a compound of the formula or a pharmaceutical acceptable salt thereof as claimed in the scope of claim 2 or in the manufacture of a medicament for the treatment or prevention of Alzheimer's disease. μ 79526-990408.DOC This paper size applies to the Chinese National Standard (CNS) Α4 specification (210X 297 public)